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| TITLE |
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Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
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| AUTHORS |
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Christopher P Cannon, E Braunwald, Carolyn H McCabe, Daniel J Rader, J L Rouleau, Rene Belder, Steven V Joyal, Karen A Hill, M A Pfeffer, Allan M Skene
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| PUBLICATION INFORMATION |
Journal Name: The New England Journal of Medicine
Volume: 350(15)
Pages: 1495-504
Date Published: 04/08/2004
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| ABSTRACT/REVIEW |
What were the researchers trying to learn in this study?
The study was designed to show that standard dose treatment with pravastatin (pra' va stat in) to lower cholesterol was not less effective than treatment with higher dose atorvastatin (a-TOR-va-stat-in) in terms of survival, heart attacks, unstable angina requiring hospitalization, or the need for balloon angioplasty or bypass surgery.
Pravastatin (Pravachol®) and atorvastatin (Lipitor®) are used with dietary changes aimed at limiting cholesterol and fat intake to reduce the amount of cholesterol and certain fatty substances in your blood. They work by blocking an enzyme that is needed by the body to make cholesterol, thereby reducing the amount of cholesterol in the blood.
What did they find?
The results showed a advantage for patients in the high-dose atorvastatin group across all subgroups studied, including men and women, patients with unstable angina and those who had had heart attacks (myocardial infarction), and those with and without non-insulin-dependent diabetes (diabetes mellitus).
In their analysis of the data, the researchers found that after two years 26.3 percent of the patients in the pravastatin group had either died, experienced a heart attack, undergone either angioplasty or bypass surgery, or had been hospitalized for unstable angina. That compared to 22.4 percent in the atorvastatin group who experienced any of those events. This difference was enough in statistical terms to show that the two drugs were not equivalent, but that higher doses of atorvastatin provided an advantage to patients over the standard dose pravastatin.
Patients in the pravastatin group achieved an average (median) LDL cholesterol level of 95 mg per deciliter (2.46 mmol per liter) compared to a LDL level of 62 mg per deciliter (1.60 mmol per liter) achieved by the high-dose atorvastatin group.
The percentage of patients who discontinued the drug due to side effects was about the same for both groups. After one year, 21.4% of the pravastatin group and 22.8% of the atorvastatin group had discontinued the treatment. After 2 years, 33% of the pravastatin group and 30.4% of the atorvastatin group had stopped taking the drug. Although both drugs were generally well tolerated, there were significantly more liver related side effects with high-dose atorvastatin than with standard-dose pravastatin.
Who was studied?
Between Nov. 15, 2000, and Dec. 22, 2001, 4,162 patients were enrolled at 349 sites in eight countries. The average age was 58 years, and 22 percent were women. Before the cardiac event that brought them into the trial, 18% of patients had had a heart attack (myocardial infarction), 11% percent had previously undergone coronary-artery bypass surgery, and 18% had type II non-insulin-dependent diabetes mellitus.
Men and women who were at least 18 years old were eligible for inclusion if they had been hospitalized for an acute coronary syndrome – either acute myocardial infarction or high-risk unstable angina – in the preceding 10 days. Patients had to be in stable condition and were to be enrolled after a balloon angioplasty or bypass surgery (percutaneous revascularization procedure) if one was planned. Finally, patients had to have a total cholesterol level of 240 mg per deciliter (6.21 mmol per liter) or less, measured at the local hospital within the first 24 hours after the onset of the acute coronary syndrome or up to six months earlier if no sample had been obtained during the first 24 hours.
How was the study done?
The researchers compared standard therapy (40 mg of pravastatin daily) with intensive therapy (80 mg of atorvastatin daily) based on the number of deaths from any cause, myocardial infarctions, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. They followed the patients for 18 to 36 months for an average of 24 months.
Eligible patients were randomly assigned to receive either 40 mg of pravastatin or 80 mg of atorvastatin daily in a double-blind, double- dummy fashion, meaning all participants took two pills and neither they nor their doctors knew which pills were which drugs. Patients were seen for follow-up visits and received dietary counseling at 30 days, at 4 months, and every 4 months thereafter until their final visit in Aug. or Sept. 2003.
The protocol specified that patients were to receive standard medical and interventional treatment for acute coronary syndromes, including aspirin at a dose of 75 mg to 325 mg daily, with or without anticlotting medications (clopidogrel (Plavix®) or warfarin (Coumadin®)). Patients were not permitted to be treated with any lipid-modifying therapy other than the study drug.
What did researchers know before starting this study?
Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. The doses of statins used in earlier trials reduced low-density lipoprotein (LDL) cholesterol levels by 25 to 35 percent, and current guidelines recommend a target LDL cholesterol level of less than 100 mg per deciliter (2.59 mmol per liter) for patients with established coronary artery disease or diabetes. It is not clear whether lowering lipid levels further would increase the clinical benefit.
Why did they do it?
The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial was designed to compare standard LDL cholesterol lowering with more intensive LDL cholesterol lowering to determine which approach was better in terms of preventing death or major cardiovascular events in patients with an acute coronary syndrome.
What did the researchers say their study results mean?
The researchers concluded that after an acute coronary syndrome, the most effective target LDL cholesterol level may be lower than that recommended in current guidelines.
They also noted that patients in clinical practice generally have more coexisting conditions than did the patients in this trial, and they may not tolerate a high-dose statin regimen as well as these patients did. Thus, clinicians must take these factors into account when applying the results of this trial in clinical practice.
Editor's note:
This study was funded by Bristol-Myers Squibb and Sankyo, which market Pravachol, as a "non-inferiority" trial, meaning they hoped to show that Pravachol was at least as effective as the competing product.
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